Pharmaceutical compositions for acute glucocorticoid therapy

ABSTRACT

The present invention relates to glucocorticoid-containing pharmaceutical compositions or kits for use in acute emergency situations where acute glucocorticoid therapy is required. Notably, the invention relates to pharmaceutical compositions and kits that are designed to be administered by non-medically trained persons outside a hospital or another medical or clinical setting. The invention also relates to a method for treating a disorder requiring acute glucocorticoid therapy by providing a fast onset of action of a glucocorticoid

FIELD OF THE INVENTION

The present invention relates to glucocorticoid-containingpharmaceutical compositions or kits for use in acute emergencysituations where acute glucocorticoid therapy is required. Notably, theinvention relates to pharmaceutical compositions and kits that aredesigned to be administered by non-medically trained persons outside ahospital or another medical or clinical setting. The invention alsorelates to a method for treating a disorder requiring acuteglucocorticoid therapy by providing a fast onset of action of aglucocorticoid.

BACKGROUND OF THE INVENTION

Glucocorticoids are important steroids for intermediary metabolism,immune function, musculoskeletal and connective tissue as well as thebrain. The importance of the glucocorticoids is best understood inpatients with glucocorticoid deficiency. In such patients, the one-yearsurvival rate was only 20% in the 1950s before the availability ofglucocorticoid replacement therapy. The major use of glucocorticoids inclinical practice began, however, with their use in the treatment ofrheumatoid arthritis in the 1940s. Both natural and syntheticglucocorticoids have been employed in the management of a wide varietyof conditions and they play a crucial part of many emergency treatmentsinvolving allergic and inflammatory disorders.

The endogenous glucocorticoids are steroids predominantly produced inthe adrenal cortex. The main glucocorticoid in the body is cortisol. Theproduction and secretion of cortisol is governed by a complex and highlyefficient system that includes the hypothalamus, pituitary and theadrenal glands i.e. hypothalamic-pituitary-adrenal axis (HPA). Cortisolsecretion has a circadian release rhythm with peak values in earlymorning and trough values at midnight. The HPA axis is also activated byseveral physical and psychological stressors. Thus, under stressconditions, such as physical activity, fever, surgery or mental stress,the serum cortisol concentration is increased.

Adrenocortical deficiency results in a number of complex symptoms thatresults from deficiency of adrenocortical hormone activity. It may be ofa primary type as a result of a disease in the adrenal cortex, asecondary (central) type due to the specific pathology in thehypothalamus and/or the pituitary gland, or a tertiary type due to asuppressed HPA axis after long-term high dose glucocorticoid treatment.

The onset of adrenocortical insufficiency may vary from insidious to anacute life-threatening situation with severe salt and water deficit,which leads to shock and death if not treated fast and adequately.

Therapy of e.g. acute adrenal crisis requires that the one or moreglucocorticoids quickly enter (are absorbed) into the systemiccirculation at a therapeutically effective concentration interval(therapeutic window). Although a number of variousglucocorticoid-containing pharmaceutical compositions already are on themarket, most of these are not suitable for the treatment of a disorderrequiring acute glucocorticoid therapy as they either result in a tooslow appearance in the systemic circulation (e.g. conventional tablets)or in a too low, if any, glucocorticoid serum level (manyglucocorticoid-containing pharmaceutical compositions are intended forlocal treatment e.g. in the nose or on the skin).

There are today two ways of administering glucocorticoids in medicalemergencies. One is the parenteral route where an intravenous (IV)infusion has to be set up or a deep intramuscular (IM) injection has tobe given. However, one disadvantage of this administration is that an IVroute can be challenging to establish particularly in patients withcompromised peripheral circulation. Furthermore, parenteraladministration requires qualified personnel and is therefore limited towell-crewed ambulances and in-hospital settings.

The other administration route is traditionally by oral administrationusing a dissolvable betamethasone tablet in water. This route is mainlyused in outpatient clinics and for patient self-medication. However, thedisadvantages are the considerable lag-time when preparing the solutionand the time from intake until a significant serum level of the drug isobtained. The maximum plasma concentration (C_(max)) is usually reachedwithin 1 to 3 hours after administration (T_(max)) It is also well knownthat the onset of intestinal absorption cannot be earlier than 0.5 hourfor these oral immediate release products of a rapidly dissolved andrapidly absorbed drug (a class I drug according to the FDA'sBiopharmaceutics Classification System), the gastric emptying being veryvariable both in the fasted and fed state. Furthermore, it is mandatorythat the patient is conscious and has unaffected ability to swallow thesolution since a weak gastrointestinal motility results in a furtherdelay in gastric emptying and reduced intestinal absorption (both rateand extent).

Examples of such cumbersome oral administrations are obtained inpatients with acute laryngitis, patients with severe distress due tobreathlessness, children with croup or severe angioedema, and inpatients with gastroenteritis where gastrointestinal absorption isuncertain.

Accordingly, it would be of great therapeutic advantage to developpharmaceutical compositions that enable self-administration by patientsand administration to patients by non-medically trained persons outsideof a hospital, clinic, ambulance, paramedical or similar medicalsettings and at the same time result in a sufficient treatment of adisorder requiring acute glucocorticoid therapy (e.g. acute adrenalcrises) by providing a fast onset of action after administration.Moreover, there is also a need for pharmaceutical compositions that canbe administered to a patient who e.g. is unconscious or otherwise unableto swallow a composition (e.g. a tablet or solution) and that does notrequire medically trained personnel or need be done in a medicalsetting.

DETAILED DISCLOSURE OF THE INVENTION

The present invention meets the above-described needs by providing apharmaceutical composition comprising one or more glucocorticoids forsubstantially immediate release, wherein at least about 60% of the oneor more glucocorticoids are released from the composition within thefirst 30 min after start of an in vitro dissolution test according toUSP employing USP Dissolution Apparatus No. 2 (paddle), 50 rpm and asuitable dissolution medium such as, e.g., water, simulated saliva orsimulated intestinal fluid without enzymes, and wherein a glucocorticoidserum level of a subject of at least 20% of C_(max) is reached within 20min after administration of the composition via a mucosa of the subject.

The dissolution medium can be chosen depending on the type ofcomposition in question. Accordingly, water or simulated saliva can beused for compositions intended for administration to the oral cavity. Aperson skilled in the art will know how to chose the right dissolutionmedium depending on the formulation in question. Normally a dissolutionmedium based on water and adjusted to a pH in the range of from pH 4.5to about 8 is suitable irrespective of whether the compositions areintended for administration via nasal, rectal, vaginal mucosa.

In the present context the term “substantially immediate release” isintended to include all types of release which differ from the releaseobtained from plain tables and provide a release, which is faster thanthat obtained from plain tablets. In particular, the term is related toa rapid release of the one or more glucocorticoids in an in vitrodissolution test according to USP employing USP Dissolution ApparatusNo. 2 (paddle), 50 rpm and simulated intestinal fluid without enzymes asdissolution medium.

The term “C_(max)” denotes the average maximum serum/plasma/bloodconcentration or serum/plasma/blood level obtained after administrationof the composition to at least six normal healthy human subjects.

The term “via a mucosa” indicates that the one or more glucocorticoidsmust enter into the systemic circulation in order to obtain the desiredeffect and that the administration route is different from that oftopical, intravenous and intramuscular administration.

In another aspect, the invention relates to a kit for treating a subjectsuffering from a disorder requiring acute glucocorticoid therapycomprising one or more containers for housing a pharmaceuticalcomposition according to the invention and instructions for use thereof.In a specific embodiment, the one or more containers are in the form ofblisters or blister packs.

In a further aspect, the invention relates to a method for treating asubject suffering from a disorder requiring acute glucocorticoidtherapy, the method comprises administering via a mucosa of the subjectan effective amount of one or more glucocorticoids to obtain a fast risein the glucocorticoid serum level to at least 20% of C_(max) within 20min after administration.

In a still further aspect, the invention relates to the use of an amountof one or more glucocorticoids for the preparation of a pharmaceuticalcomposition or kit as defined herein for the treatment of a disorderrequiring acute glucocorticoid therapy by providing a fast rise in theglucocorticoid serum level to at least 20% of C_(max) within 20 minafter administration via a mucosa.

As mentioned above, in order to obtain a fast onset of action it isrequired that a fast rise of glucocorticoid serum level is obtainedafter administration of a composition of the invention. Accordingly, inspecific embodiments least 40% of C_(max) is reached within 30 minand/or at least 75% of C_(max) is reached within 45 min afteradministration of the composition via a mucosa of the subject.

Normally, T_(max) (i.e. the time it takes to obtain the maximumserum/plasma/blood concentration in the serum/plasma/blood concentrationtime profile) is reached within 60 min after administration of thecomposition via a mucosa of the subject. T_(max) is typically within arange of from about 30 to about 75 min such as in a range of from about45 to about 60 min.

As mentioned above, the pharmaceutical compositions and kits of thepresent invention are suitable for use in the treatment of a disorderrequiring acute glucocorticoid therapy. Examples of such disorders areacute adrenal crises relating to a primary, secondary or tertiaryadrenal insufficiency, an anaphylactic reaction, an Addison crisis, astatus asthmaticus, a blood transfusion reaction, a brain edema, acutekidney transplant rejection, systemic lupus erythematosus or a severeallergic reaction. Other examples include inflammatory disorders,autoimmune disorders, or medical disorders in which a glucocorticoidforms a part of the first line emergency medical treatment or intenseshort-time medical treatment. Specific examples of disorders that can betreated according to the present invention are given in the following.

Active Substance, Dosage and Administration Routes

In the present context, the term “glucocorticoid” or“glucocorticosteroid” is intended to denote a therapeutically,prophylactically and/or diagnostically active glucocorticoid or aglucocorticoid that has physiologic effect. The term is intended toinclude the glucocorticoid in any suitable form such as e.g. apharmaceutically acceptable salt, complex, solvate, ester, activemetabolites or prodrug thereof of in any physical form such as, e.g., inthe form of crystals, amorphous or a polymorphous form or, if relevant,in any stereoisomer form including any enantiomeric or racemic form, ora combination of any of the above. The glucocorticoid may be a syntheticglucocorticoid.

The one or more glucocorticoids used according to the invention areselected from the group consisting of hydrocortisone, cortisone,prednisolone, prednisone, methylprednisone, triamcinolone,paramethasone, betamethasone, dexamethasone and fludrocortisoneincluding pharmaceutically acceptable esters, salts, complexes andmixtures thereof. In a preferred embodiment of the invention, theglucocorticoid is betamethasone.

Specific examples of pharmaceutically acceptable salt suitable for useaccording to the invention are phosphates, succinates, lysinates,acetates, cypionates, valerates, hemisuccinates, butyrates andtrometamole salts.

As the glucocorticoid is intended for immediate release, the releaseand/or absorption into the systemic circulation takes place already inthe oral cavity in the case the composition is administered orally. Insuch cases, the glucocorticoid of choice for the first part may be anyother than hydrocortisone (as such) or cortisone as these two activesubstances have a bitter taste. However, these substances may beemployed provided that a sufficient taste masking is obtained. In theparagraph relating to “Pharmaceutically acceptable excipients”taste-masking is discussed in more detail. Accordingly, the one or moreglucocorticoids of the first part may have an acceptable taste, may betasteless or it may be effectively taste-masked.

Furthermore, in specific embodiments of the invention, theglucocorticoid used may be a readily water-soluble glucocorticoid (e.g.a water-soluble salt of the glucocorticoid) in order to ensure a fastdissolution of the glucocorticoid from the composition.

In a preferred embodiment of the invention the glucocorticoid ishydrocortisone trometamole (or succinate) due to its high solubility inwater, which in turn leads to a rapid absorption into the systemiccirculation.

Dosage

In general, the dosage of the glucocorticoids present in a compositionaccording to the invention depends inter alia on the specific drugsubstance, the age and condition of the patient and of the disease to betreated.

The term “hydrocortisone equivalents” is used herein to define theamount in mg of a specific glucocorticoid that corresponds to 1 mg ofhydrocortisone for the purpose of glucocorticoid therapy as generallyunderstood by medical practitioners. The term is based on the fact thatthe individual glucocorticoids have different potency and in order toachieve a desired therapeutic effect different doses of the individualglucocorticoids are required. Equivalent doses of the glucocorticoidscan be calculated based on the following table.

Hydrocortisone equivalent (1 mg of the glucocorticoid corresponds to thelisted amount in mg of Glucocorticoid Equivalent amount (mg)hydrocortisone) Cortisone acetate 25 0.8 Hydrocortisone 20 1Prednisolone 5 4 Prednisone 5 4 Methylprednisolone 4 5 Triamcinolone 4 5Paramethasone 2 10 Betamethasone 0.75 26.66 Dexamethasone 0.75 26.66Fludrocortisone 0.05 400

In general, a pharmaceutical composition according to the inventioncontains a total amount of the one or more glucocorticoids expressed ashydrocortisone of from about 1 to about 200 mg. In specific embodiments,the total amount of the one or more glucocorticoids expressed ashydrocortisone is from about 1 to about 175 mg such as, e.g., from about1 to about 150 mg, from about 1 to about 100, from about 1 to about 75mg, from about 1 to about 70 mg, from about 1 to about 60 mg, from about5 to about 50 mg, from about 5 to about 40 mg or from about 10 to about30 mg.

More specifically, normal dose ranges are given below for acuteglucocorticoid therapy

Hydrocortisone 1-200 mg; in acute adrenal crises about 100 mg Cortisone1-200 mg such as about 100 mg Betamethasone 1-20 mg; in increasedintracranial pressure e.g. brain oedema about 4 mg daily In chemotherapyor radiation induced nausea 4-8 mg Prednisolon 1-100 mg; such as from 1to 30 mg daily; in severe cases 50-60 mg/day Dexamethasone 0.1-6 mg suchas 0.5-2 mg or 1.5-3 mg; in severe cases up to 6 mg/day Fludrocortisone0.05-5 mg; in Addison disease to correct inadequate electrolyte balance0-05-0.2 mg daily; Cortical adrenal hyperplasia (“salt losingadrenogental syndrome”) 0.1-0.2 mg Prednisone 10-100 mg such as 50 mgMethylprednisolone 2-40 mg such as 2-20 mg

In the following are given suitable doses of the individualglucocorticoids in various treatment regimens.

Acute asthma - adults betamethasone 4-8 mg prednisolone 30-60 mgmethylprednisolone 40 mg Acute anaphylaxia - adults betamethasone 5 mgup to 20 mg hydrocortisone 200 mg dexamethasone 4-20 mg-80 mg Acuteanaphylaxia - children hydrocortisone 100-200 mg Septic shock - adultshydrocortisone 200-300 mg/day methylprednisone 30 mg/kg Acute bacterialmeningitis dexamethasone 0.3 mg/kg/dose (max 10 mg) × 4 times daily for2-4 days betamethasone 8 mg × 4 times daily Acute RSV (respiratorysyncytial virus) infection with bronchiolitis in children betamethasone4-6 mg Acute croup - children betamethasone 4-6 mg Mononucleosis withcomplications (airway obstruction, thrombocytopenia or haemolyticalanaemia) betamethasone 5-6 mg Tonsillitis/peritonsillitis - childrenwith airway obstruction betamethasone 4-6 mg

A composition according to the invention is designed to provide a fastonset of action and upon administration a fast rise in glucocorticoidserum/plasma/blood level is obtained. In the case hydrocortisone is usedas the glucocorticoid a serum level of at least about 200 nmol/l isobtained within 20 min after administration. In the case that anotherglucocorticoid than hydrocortisone is used, a person skilled in the artwill know how to determine suitable equivalent serum/plasma/bloodconcentrations.

For example, hydrocortisone can be rapidly released from a compositionduring a time period of from about 0 to abut 30 minutes afteradministration and 5-10 mg of hydrocortisone can be rapidly administeredas an extra dose in conjunction with fever etc in patients with adrenalinsufficiency. Likewise, 5-20 mg of betamethasone can be rapidlyreleased for most indications in which a rapid glucocorticoid effect isof value.

Administration Routes

As mentioned above, the one or more glucocorticoids used according tothe invention are administered to the subject (preferably a human) via amucosa into the systemic circulation. In particular, in specificembodiments of the invention, the mucosa is the mucosa in the oralcavity, the nose, the rectum or in the vagina or via pulmonary,bronchial or respiratory mucosa and epithelia. Preferably, the mucosa isthe oral mucosa.

FIGS. 11 and 12 show sites of oral mucosal administration suitable foruse. Four well-defined sites may be used, namely

“buccal” administration that includes the term “labial” administrationand is used for administration of a pharmaceutical composition to amucosa between the gums (gingiva) and the inside of the cheeks;“sublingual” administration that refers to administration of apharmaceutical composition under the tongue;“palatal” administration that refers to administration of apharmaceutical composition to the hard and/or soft palate; and“gingival” administration that refers to administration of apharmaceutical composition to the upper and/or lower gingiva.

All the above-mentioned sites are suitable for use to obtain a very fastonset of action due to a rapid absorption (transport of active drug)into the systemic circulation. In specific embodiments of the inventionthe buccal administration route is preferred, i.e. administration of acomposition to the oral mucosa between the gums and the inside of thecheeks and thus enabling the absorption to take place from two sites,namely the gingival mucosa and the buccal mucosa.

Pharmaceutical Compositions

In the following is given a description of pharmaceutical compositionsaccording to the invention.

Release of the One or More Glucocorticoids

A rapid release of the one or more glucocorticoids is necessary in orderto obtain a fast onset of action after administration via a mucosa wherethe glucocorticoid is rapidly absorbed (transported) into the systemiccirculation. Accordingly a general requirement is that at least 60% ofthe one or more glucocorticoids contained in the composition must bereleased within 30 min when tested in an in vitro dissolution test asdefined herein. Specific embodiments of the composition fulfil one ormore of the requirements given in the following table. In general, it ispreferred that the requirement stated within 30 min after start of thedissolution test is fulfilled. In preferred embodiments, at least 70% orat least 80% of the one or more glucocorticoids contained in thecomposition are released within the first 20 min of the dissolutiontest.

% hydrocortisone equivalents released time after start of the (based onthe content in the dissolution test composition) within 30 min at leastabout 60% such as, e.g., at least about 70%, preferably at least about80% or more preferably at least about 90% within 20 min at least about60%, preferably at least about 70%, at least about 80% or even morepreferred at least about 90% within 15 min at least about 60% such as,e.g., at least about 70%, preferably at least about 80% or at leastabout 90% within 10 min at least about 60% such as, e.g., at least about70%, preferably at least about 80% or at least about 90% within 5 min atleast about 60%

In specific embodiments (cf. the examples herein) more than 50% of theone or more glucocorticoids can be released within 2 min, between 50 and90% can be released within 5-8 min, and more than 90% of the dose can bereleased within 15 min.

A pharmaceutical composition according to the invention is designed forsystemic administration via a mucosa. In a preferred embodiment themucosa is the mucosa in the oral cavity.

The pharmaceutical composition may be in any suitable form includingliquid, semi-solid or solid form.

In a preferred aspect of the invention the pharmaceutical composition isin the form of a dosage form such as a unit dosage form.

Examples of compositions according to the invention suitable foradministration via the oral mucosa into the systemic circulation aretypically solid or semi-solid dosage forms. The solid dosage form istypically selected from the group consisting of granules, beads, pelletsand powders and—when presented in unit dosage form—it may be in the formof a tablet including a chewable tablet, a suckable tablet, aneffervescent tablet, a sublingual tablet, a rapid-burst tablet, animmediate release tablet, a rapidly dissolvable tablet, melt tablets,lozenges, pastilles or it may be presented in a more candy-like form, orthe like.

A pharmaceutical composition for administration via the oral mucosa intothe systemic circulation may also be in the form of a spray, a wafer, afilm, a gel, a hydrogel, a patch, a gingival patch, a bioadhesive patch,a sachet, a solution, an inhaler or the like.

Examples of compositions according to the invention suitable foradministration via the mucosa in the nose into the systemic circulationare typically in the form of nasal sprays, nasal aerosols, nasalsolutions including nasal drops and the like.

Examples of compositions according to the invention suitable foradministration via the pulmonary, bronchial and respiratory mucosa andepithelia into the systemic circulation are inhalers including powderinhalers.

Examples of compositions according to the invention suitable foradministration via the mucosa in the rectum or the vagina into thesystemic circulation include suppositories, vagitories, clysmas etc.

A pharmaceutical composition according to the invention may also havebio/mucoadhesive properties. The absorption of drugs into the systemiccirculation from a mucosal drug delivery system is significantlyimproved if a mucosal bioadhesive component is added in the formulation.It will prevent both swallowing and create a high local concentration ofthe glucocorticoid adjacent to the absorption site. The mucoadhesivecomponent will be mixed in an appropriate way together with theglucocorticoid and other ingredients in the dosage form. The term“bio/mucoadhesive is used to denote that the composition is able toreversible adhere to a biological mucosa. In some cases abio/mucoadhesion promoting agent is included in the composition topromote adherence to the mucosa.

In the term bio/mucoadhesion promoting agent mucoadhesion andbioadhesion are used interchangeable even if bioadhesion may have awider definition meaning that an adhesion to any biological featureavailable at the mucosa takes place. If present, the bio/mucoadhesionpromoting agent may be a polymeric substance, preferable a substancehaving an average molecular weight above 5 kD. The hydration property iscrucial for the bio/mucoadhesion forces and therefore a rapid swellingof the polymer will initiate the bio/mucoadhesion process. A swellingfactor by volume when brought into contact with the saliva fluid shouldbe between 10 and 20.

A pharmaceutical composition according to the invention typicallycontains one or more pharmaceutically acceptable excipients. A generaldescription of pharmaceutically acceptable excipients suitable for usein a composition according to the present invention is given in theparagraph under the heading “Pharmaceutically acceptable excipients”.Depending on the specific kind of dosage form a person skilled in theart will know which kinds of excipients to choose, if necessary guidedby the teaching in handbooks like Remington's Pharmaceutical Science andHandbook of Pharmaceutical Excipients. In the following is given adescription of specific kinds of excipients suitable for use in theformulation of compositions in the form of film or patches especiallyfor administration to the oral cavity.

When the pharmaceutical composition is in the form of a film, patch,wafer, gel, sachet, gingival patch or the like it may contain apharmaceutically acceptable excipient selected from the group consistingof an acrylic polymer including a derivative thereof, a cellulosederivative, modified starch, polyethylene oxide, chitosan, gelatin,sodium alginate, pectin, scleroglucan, xanthan gum, guar gum, orpoly-co-(methyl vinyl ether-maleic anhydride), alone or in combinationsthereof. The cellulose derivative may be selected from the groupconsisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, sodium carboxymethyl cellulose, methylcellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose,microcrystalline cellulose, modified cellulose gum, or crosscaramellose.

A pharmaceutical composition according to the invention may also containthe one or more bio/mucoadhesion promoting agents. Normally suchbio/mucoadhesion promoting agents are present in concentration of fromabout 0.1 to about 25% w/w. Examples of bio/mucoadhesion promotingagents include polymers including synthetic polymers, natural polymersand derivatives thereof, and mixtures thereof. The polymer may beselected from a carbomer, a polyethylene oxide, a poly co-(methylvinylether/maleic anhydride, and mixtures thereof; or it may be apolysaccharide. The polysaccharide may be selected from the groupconsisting of gelatin, sodium alginate, pectin, scleroglucan, xanthangum; guar gum, microcrystalline cellulose, crosscaramellose,hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, ethyl hydroxyethyl cellulose,carboxymethyl cellulose, sodium carboxymethyl cellulose, moderatelycross-linked starch, and chitosan.

A pharmaceutical composition according to the invention may alsocontaining a dissolution promoting agent. If present, a dissolutionpromoting agent is present in a concentration of from about 0.05 toabout 5% w/w of the total weight of the composition. The dissolutionpromoting agent may be selected from the group consisting of sodiumlauryl sulphate, a polysorbate, a bile acid, a bile salt, a salt ofcholic acid or cholanic acid, isopropyl myristate, methyl laurate, oleicacid, oleyl alcohol, glycerol monoleate, glycerol dioleate, glyceroltrioleate, glycerol monostearate, glycerol monolaurate, propylene glycolmonolaurate, sodium dodecyl sulfate, and a sorbitan ester.

In specific embodiment the one or more glucocorticoids in a compositionof the invention are present as microparticles or nanoparticles. Ingeneral, he mean particle size of such particles is 10 μm or less.Furthermore, the micro- or nanoparticles may be encapsulated such ascoated with a coating comprising a lechitin or a lechitin basedcompound.

When the glucocorticoid is present in the form of micro- ornanoparticles, a pharmaceutical composition according to the inventionmay also comprise a disintegrating agent. Such agents promote thedispersion of microparticles of the glucocorticoid over theadministration site in for example the labial and gingival mucosa.Examples of pharmaceutically acceptable disintegrating agents arecross-linked polyvinylpyrrolidone, carboxymethyl starch, natural starch,microcrystalline cellulose, and cellulose gum. If present, it isnormally used in a concentration of from 0.5 to 10 w/w based on thetotal weigh of the composition Different pharmaceutical excipients, suchas mannitol and lactose, have been found to be particularly suitable asexcipients.

As mentioned above, the pharmaceutical composition according to theinvention may further comprise a taste-masking agent. Examples of ataste-masking agent are e.g. menthol, peppermint, vanillin, a terpenebased compound, or an artificial sweetener. In a specific embodiment,the one or more glucocorticoids are taste masked by incorporation intoan inclusion complex by means of alpha-, beta-, or gamma-cyclodextrins,preferably by beta-cyclodextrins.

In general, the composition of the invention contains from 0.05 up to 50weight percent such as, e.g., from 0.05 up to 40 weight percent, 0.05 upto 30 weight percent or from about 0.05 up to 20 weight percent ofglucocorticoid. More preferably, the compositions contains from 0.05 to10 weight percent of glucocorticoid, and especially from 0.1 to 5 weightpercent. The contents can also be expressed as the amount ofglucocorticoid in a dose unit of the composition, such as a tablet. Inthis connection a dose refers to the therapeutically amount of the atleast one glucocorticoid, or its derivative, which is to be administeredat one time. When the glucocorticoid is used in the form of apharmaceutically acceptable salt, these percentages and amounts shouldbe recalculated accordingly.

Pharmaceutically Acceptable Excipients

In the present context the terms “pharmaceutically acceptableexcipients” are intended to denote any material, which is inert in thesense that it substantially does not have any therapeutic and/orprophylactic effect per se. Such an excipient may be added with thepurpose of making it possible to obtain a pharmaceutical, which haveacceptable technical properties.

Examples of suitable excipients for use in a solid dosage form accordingto the invention include fillers, diluents, disintegrants, binders,lubricants etc. or mixture thereof. As the individual parts of acomposition or kit according to the invention are used for differentpurposes (e.g. immediate and extended release), the choice of excipientsis normally made taken such different uses into considerations. A personskilled in the art will know which kinds of pharmaceutically acceptableexcipients that are suitable choices depending on the specific dosageform in question. Other pharmaceutically acceptable excipients forsuitable use are e.g. acidifying agents, alkalising agents,preservatives, antioxidants, buffering agents, chelating agents,colouring agents, complexing agents, emulsifying and/or solubilizingagents, flavours and perfumes, humectants, sweetening agents, wettingagents etc.

Examples of suitable fillers, diluents and/or binders include lactose(e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®, variousgrades of Pharmatose®, Microtose® or Fast-Floc®), microcrystallinecellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® orSolka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (lowsubstituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E, Fand K, Metolose SH of Shin-Etsu, Ltd, such as, e.g. the 4,000 cps gradesof Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F andMetolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K;and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH),methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C,Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodiumcarboxymethylcellulose, carboxymethylene,carboxymethylhydroxyethylcellulose and other cellulose derivatives,sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starchesor modified starches (including potato starch, maize starch and ricestarch), calcium phosphate (e.g. basic calcium phosphate, calciumhydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate,calcium carbonate, sodium alginate, collagen etc.

Specific examples of diluents are e.g. calcium carbonate, dibasiccalcium phosphate, tribasic calcium phosphate, calcium sulfate,microcrystalline cellulose, powdered cellulose, dextrans, dextrin,dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch,pregelatinized starch, sucrose, sugar etc.

Specific examples of disintegrants are e.g. alginic acid or alginates,microcrystalline cellulose, hydroxypropyl cellulose and other cellulosederivatives, croscarmellose sodium, crospovidone, polacrillin potassium,sodium starch glycolate, starch, pregelatinized starch, carboxymethylstarch (e.g. Primogel® and Explotab®) etc.

Specific examples of binders are e.g. acacia, alginic acid, agar,calcium carrageenan, sodium carboxymethylcellulose, microcrystallinecellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum,hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone,pregelatinized starch etc.

Glidants and lubricants may also be included in the composition.Examples include stearic acid, magnesium stearate, calcium stearate orother metallic stearate, talc, waxes and glycerides, light mineral oil,PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils,corn starch, sodium stearyl fumarate, polyethylene glycols, alkylsulfates, sodium benzoate, sodium acetate etc.

Other excipients which may be included in a composition of the inventionare e.g. flavoring agents, coloring agents, taste-masking agents,pH-adjusting agents, buffering agents, preservatives, stabilizingagents, anti-oxidants, wetting agents, humidity-adjusting agents,surface-active agents, suspending agents, absorption enhancing agents,agents for modified release etc.

The composition or kit components according to the invention may also becoated with a film coating, a protective coating, an anti-adhesivecoating etc.

A composition according to the invention may also be coated in order toobtain suitable properties e.g. with respect to taste-masking of the oneor more glucocorticoids. The coating may also be applied as a readilysoluble film. The coating may be applied on single unit dosage forms(e.g. tablets) or it may be applied on a multiple-unit dosage form or onits individual units.

Suitable coating materials are e.g. methylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers,ethylcellulose, cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, polyvinylalcohol,sodium carboxymethylcellulose, cellulose acetate, cellulose acetatephthalate, gelatin, methacrylic acid copolymer, polyethylene glycol,shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax,glyceryl monostearate, zein.

Plasticizers and other ingredients may be added in the coating material.The same or different active substance may also be added in the coatingmaterial.

Taste Masking

In general, it is difficult in most cases to prepare a formulation fororal mucosa or nasal administration with satisfactory safety andstability from a drug having irritating properties or capable of formingmolecular aggregates, although it depends on the kind of the drug used.In the case of hydrocortisone, the base has a distinctively bitter tasteand a formulation has to be taste masked in order to be applicable forrepeated use.

The taste masking agent can be a menthol, a peppermint, a vanillin, or aterpene based compound. In addition, the taste masking agent can be anartificial sweetener, e.g. sorbitol, xylitol or aspartame. Taste maskingcan also be achieved by microencapsulation of the glucocorticoid asparticles. This is for example accomplished with lecithin basedcompounds. The taste masking agent is carefully mixed with the activedrug in order to be present both at the surface and within theadministration formulation. Taste masking can also be achieved byformation of inclusion complexes with cyclodextrins.

Typical examples of the cyclodextrin compound are alpha.-cyclodextrin,beta.-cyclodextrin, .gamma.-cyclodextrin, hydroxypropyl.beta.-cyclodextrin, dimethyl beta.-cyclodextrin, maltosyl.beta.-cyclodextrin and .beta.-cyclodextrin sulfate. Particularlypreferred are .alpha.-cyclodextrin, .beta.-cyclodextrin and.gamma.-cyclodextrin. These cyclodextrin compounds may be used alone orin combination.

The amount of cyclodextrin compound to be used may vary with itssolubility and the concentration of hydrocortisone. It is, however,desirable that the amount of cyclodextrin compound is 0.5 to 4.0 moles,preferably 2.0 to 4.0 moles, as much as the mole of hydrocortisone.

Method Aspect

A pharmaceutical composition or a kit according to the invention issuitable for use in the treatment of a subject such as a mammalincluding a human suffering from a disorder requiring acuteglucocorticoid therapy.

Accordingly, in a separate aspect the invention relates to a method fortreating a subject suffering from a disorder requiring acuteglucocorticoid therapy, the method comprises administering via a mucosaof the subject an effective amount of one or more glucocorticoids toobtain a fast rise in the glucocorticoid serum level to at least 20% ofC_(max) within 20 min after administration.

Normally, it is preferred that at least 40% of C_(max) is reached within30 min after administration in order to obtain a fast onset of action.In specific preferred embodiment, at least 75% of C_(max) is reachedwithin 45 min after administration and/or T_(max) is reached within 60min after administration of the composition via a mucosa of the subject.

Details concerning other aspects of the invention are describedhereinbefore and apply also to the method aspect of the invention.

The method according to the invention can be carried out by the patientitself or by non-medically trained persons due to the fact that the oneor more glucocorticoids are not presented in the form of a compositionfor injection or infusion. Normally, medically trained personnel canonly administer such compositions. Accordingly, the present inventionprovides a method that compared to the known treatment methods requiringacute glucocorticoids is much more simple to handle without thenecessity of specialized equipment. It is therefore contemplated thatthe present invention provides a method that enables a treatment whenthe condition of the patient requires it, i.e. there is no need forbringing the patient to a hospital or a medical clinic in order to beable to give the necessary treatment.

Moreover, due to the development of compositions that enable a fastonset of action after administration and that can be administeredwithout the need of the patient to swallow the composition (e.g.compositions of the invention in the form of films, bio/mucoadhesivecompositions, patches, gingival patches, sprays etc.), the patient maybe unconscious or otherwise unable to swallow normal tablets and stillbe correctly treated with glucocorticoids in acute situations.

Use of a Composition or a Kit According to the Invention

In another separate aspect, the invention relates to the use one or moreglucocorticoids for the preparation of a pharmaceutical composition orkit as defined hereinbefore for the treatment of a disorder requiringacute glucocorticoid therapy and to provide a serum level as definedherein.

In the above is given a detailed description of the invention relatingone or more aspects of the invention, in particular relating topharmaceutical compositions. However, all details and particularsdisclosed under this aspect of the invention apply mutatis mutandis tothe other aspects of the invention.

LEGENDS TO FIGURES

FIG. 1 shows results from Example 11. The plasma concentration-timeprofile of cortisol following a single dose administration ofcomposition A to a human subject.

FIG. 2 shows results from Example 11. The plasma concentration-timeprofile of cortisol following a single dose administration ofcomposition B to a human subject.

FIG. 3 shows results from Example 11. The plasma concentration-timeprofile of cortisol following a single dose administration ofcomposition C to a human subject.

FIG. 4 shows results from Example 12. The plasma concentration-timeprofile of cortisol following a single dose administration of film A toa human subject. Non-mucoadhesive thin-layer film, 6 cm², 10 mghydrocortisone, buccal administration. Subject has the endogenousglucocorticoid secretion suppressed by synthetic glucocorticoids.

FIG. 5 shows results from Example 12. The plasma concentration-timeprofile of cortisol following a single dose administration of film B toa human subject. Non-mucoadhesive thin-layer film, 6 cm², 11.2 mghydrocortisone acetate, buccal administration. Subject has theendogenous glucocorticoid secretion suppressed by syntheticglucocorticoids.

FIG. 6 shows results from Example 13. The plasma concentration-timeprofile of cortisol following a single dose administration ofcomposition A to a human subject. In vivo plasma profile. Mucoadhesivethin-layer film, 10 mg hydrocortisone, buccal administration. Subjecthas the endogenous glucocorticoid secretion suppressed by syntheticglucocorticoids

FIG. 7 shows results from Example 13. The plasma concentration-timeprofile of cortisol following a single dose administration ofcomposition A to a human subject. Mucoadhesive thin-layer film, 10 mghydrocortisone, buccal administration. Subject has the endogenousglucocorticoid secretion suppressed by synthetic glucocorticoids

FIG. 8 shows results from Example 14. The plasma concentration-timeprofile of cortisol following a single dose administration ofcomposition C. In vivo plasma profile. Mucoadhesive rapid-releasetablet, 10 mg hydrocortisone, buccal administration. Subject has theendogenous glucocorticoid secretion suppressed by syntheticglucocorticoids

FIG. 9 shows results from Example 15 (Composition C from Example 14).

FIG. 10 shows results from Example 15 (Composition A from Example 13).

FIGS. 11 and 12 illustrates different administration sites within theoral cavity

The invention is further illustrated in the following non-limitingexamples.

Materials

The materials used in the following examples were

Trade name Chemical substance Manufacturer Betamethasone USP/NFCarboxymetylcellulose USP/NF Chitosan glutamate USP/NF CrospovidoneUSP/NF Hydrocortisone Ph. Eur., Qual. D Aventis, Switzerland (byApoteksbolaget) Hydrocortisone acetate USP/NF Hydrocortisone 21- Ph. EurAventis, Switzerland (by hemisuccinate sodium Apoteksbolaget)2-OH-propyl-β-cyclodextrin Hydroxypropylmethylcellulose USP/NFLevomenthol USP/NF Menthol USP/NF Methocel E5 Hydroxypropyl-methyl DowChemicals, USA cellulose (by Colorcon) Methocel ® KV 100 LV USP/NF DowChemicals, USA (by Colorcon) Metolose ® Microcrystalline cellulose,USP/NF FMC Corporation Avicel ® PH-102 Paraffin powder USP/NF PEG 300USP/NF PEG 6000 Polyethylene glycol Svenska Hoechst AB PEG 400Polyethylene glycol Fluka, Switzerland Prednisolone USP/NF Polyox WSR301 Polyethylene oxide Dow Chemicals, USA Na-alginate PH157 Sodiumdihydrogen NaH₂PO₄•2 H₂O phosphate Sodium stearyl fumarate USP/NFSorbitol USP/NF Sugar USP/NF Sugar/starch seeds USP/NF Talc USP/NFTriethyl citrate USP/NF Xylitab 300 Xyrofin Kotka, Finland Xylisorb 300(Danisco Sweeteners Ltd, UK Xylitol USP/NF Roquette, France

Methods

The in vivo experiments reported herein were carried out on healthyvolunteers. At 6 pm and 11 pm the day before administration of the testcomposition, the endogenous cortisol secretion was suppressed by oraladministration of 2 mg of betamethasone. The test composition wasadministered to healthy volunteers. The volunteers were in fasted stateand were not allowed to take any food until noon. In the case a tabletis administered, it is ingested together with 200 ml of water. The testcomposition is administered between 8 am and 10 am on the day followingthe suppression of endogenous glucocorticoid secretion.

EXAMPLES Example 1 Capsules Containing an Immediate Release Pellets (IRPellets) IR Pellets

Sugar/starch seeds, diameter 0.25-0.35 mm 1 kgare coated in a fluidised bed equipped with a Wurster column with awater suspension containing

Hydrocortisone 21-hemisuccinate sodium 10% Hydroxypropylmethylcellulose, 6 cps  3% Talc 10% to a weight gain of approximately75%.

An amount of IR pellets containing 13.4 mg of hydrocortisone21-hemisuccinate sodium (approximately 70 mg) are filled into hardgelatine capsules size No 3 in a capsule-filling machine.

70 mg pellets will easily fit into a capsule size No. 3 (or even sizeNo. 4) and can be filled in a normal capsule filling machine.

Example 2 Immediate Release (IR) Tablet

IR tablets for oral or sublingual use:

Mg per tablet Betamethasone 0.4 Xylitab ® 300^(a) 40 Lactose anhydrousUSP/NF 5 Microcrystalline cellulose USP/NF 10 Crospovidone USP/NF 4Sodium stearyl fumarate 1 Water qs ^(a)Direct compression xylitol fromDanisco Sweeteners Ltd UK

Dry mix lactose and microcrystalline cellulose. Dissolve betamethasonein a small amount of water and disperse the solution over the powderblend. Mix and dry. Add Xylitab and crospovidone and dry mix until theblend is homogeneous.

Add sodium stearyl fumarate and continue blending for another 2 minutes.Compress the blend to tablets in a tablet press using 6 mm round concavepunches.

Example 3 Immediate Release (IR) Film

Thin films for administration to the oral cavity:

% by weight Prednisolone 0.75 PEG 400 USP/NF 2 Methocel E5, Dow Chemical4 Xylitol, Roquette France 1 Water up to 100

Methocel was added to approximately 90% of the total amount of distilledwater and stirred with a magnetic stirrer until Methocel was completelydissolved. PEG 400 was added under continued stirring, followed byxylitol and prednisolone. Water was added to final weight and stirringwas continued during four hours.

330 μl of the solution was pipetted into 16 mm diameter flat-bottomedPVC blisters. The solutions were allowed to dry at room temperature overnight and the blister packs were sealed with heat-seal lacqueredaluminium foil.

Example 4 Immediate Release (IR) Oral Solution

Oral solution: Prednisolone acetate 0.9 mg Sorbitol 60 mg Menthol 1.2 mgSterile water 5 ml

Make a solution and fill into a moisture tight aluminium foliatedsachet.

Example 5 Immediate Release (IR) Sublingual Spray

Sublingual spray of hydrocortisone:

mg/ml Hydrocortisone acetate 10 Carboxymetylcellulose 0.8 (0.08%)2-OH-propyl-β-cyclodextrin 40 PEG 300 5 Menthol 0.3 Sorbitol 12Levomenthol 2.0 NaH₂PO₄•2 H₂O 2 Water qs

Dissolve hydrocortisone acetate in a small amount of water. Mix with2-OH-propyl-β-cyclodextrin, let stand for 1 hour. Addcarboxymethylcellulose and mix. Add PEG 300, menthol, sorbitol,levomenthol and NaH₂PO₄.2H₂O. Add water up to final volume. Dispenseinto a spray package that delivers 0.58 ml per dose (5 mg ofhydrocortisone).

Example 6 Betamethasone IR Tablet for Peroral or Buccal Administration

Mg per tablet Betamethasone 0.4 Xylitab ® 300^(a)) 45 Microcrystallinecellulose NF 10 Crospovidone NF 4 Water qs Sodium stearyl fumarate NF 1^(a))Direct compression xylitol from Danisco Sweeteners Ltd, UK

Dissolve betamethasone in a small amount of water.

Disperse the solution over the microcrystalline cellulose. Mix and dry.

Add Xylitab and crospovidone and dry mix in a suitable mixer until ahomogeneous blend is achieved.

Then add sodium stearyl fumarate and continue mixing another twominutes. Compress the powder blend in a suitable tablet press using 6 mmround concave punches.

Example 7 Sublingual Spray of Betamethasone

mg/ml Betamethasone 0.4 Carboxymetylcellulose 0.8 (0.08%) PEG 300 5Menthol 0.3 Sorbitol 12 Levomenthol 2.0 NaH₂PO₄*2H₂O 2 Water qs

Dissolve betamethasone in a small amount of water. Addcarboxymethylcellulose and mix. Add PEG 300, menthol, sorbitol,levomenthol and NaH₂PO₄*2H₂O. Add water up to final volume.

Example 8 Sublingual Spray of Betamethasone

mg/ml Betamethasone 0.4 Chitosan glutamate 10 Menthol 0.1 Levomenthol1.5 NaH₂PO₄*2H₂O 2 Water qs

Dissolve betamethasone in a small amount of water. Add chitosanglutamate and mix. Filter through 0.2 μm membrane filter. Add menthol,levomenthol and NaH₂PO₄*2H₂O. Add water up to final volume.

Example 9 Sublingual Spray of Hydrocortisone

mg/ml Hydrocortisone acetate 10 Carboxymetylcellulose 0.8 (0.08%)2-OH-propyl-β-cyclodextrin 40 PEG 300 5 Menthol 0.3 Sorbitol 12Levomenthol 2.0 NaH₂PO₄*2H₂O 2 Water qs

Dissolve hydrocortisone in a small amount of water. Mix with2-OH-propyl-β-cyclodextrin, let stand for 1 hour. Addcarboxymethylcellulose and mix. Add PEG 300, menthol, sorbitol,levomenthol and NaH₂PO₄*2H₂O. Add water up to final volume.

Example 10 Sublingual Spray of Hydrocortisone

mg/ml Hydrocortisone acetate 10 Chitosan glutamate 102-OH-propyl-β-cyclodextrin 40 Menthol 0.1 Levomenthol 1.5 NaH₂PO₄*2H₂O 2Water qs

Dissolve hydrocortisone in a small amount of water. Mix with2-OH-propyl-β-cyclodextrin, let stand for 1 hour. Add chitosan glutamateand mix. Filter through 0.2 μm membrane filter. Add menthol, levomentholand NaH₂PO₄*2H₂O. Add water up to final volume.

Example 11 Thin-Layer Film of Hydrocortisone

% w/w Composition A: Hydrocortisone 3% Na-alginate PH157 2% Water 95% Composition B: Hydrocortisone acetate 3.4%   Na-alginate PH157 2% Water94.6%   Composition C: Hydrocortisone 3% Metolose 60SH-50 2% Water 95% 

The films were made as described in the following:

-   -   1. Amount polymer, glucocorticoid and H₂O were weighed.    -   2. The glucocorticoid was added to the water during stirring.    -   3. The formulation was kept on stirring until a suspension was        obtained.    -   4. The polymer was added to the suspension.    -   5. The formulation was kept on stirring until a uniform gel was        obtained (minimum 2 h).    -   6. 0.5 g gel was weighed in empty blisters and placed in a        heating cupboard (Drying: 25° C. for 22 h).

Table. In vitro dissolution (rotating basket 100 rpm, phosphate bufferpH=7.0, one unit per 500 ml medium) after 1, 3, 5, 10 and 15 min as apercentage of 10 mg hydrocortisone. Units with 10 mg hydrocortisone inpolymers of sodium alginate (Na-alg), hypromellose (HPMC) and approx. 7mg/unit. Two units were tested with Na-alg and HPMC. The mean value istabulated. The results in the following table reflect the rank orderregarding viscosity, i.e. HPMC has the lowest viscosity and Na-alg thehighest.

3 min, 5 min, 10 min, 15 min, Composition Polymer 1 min, % % % % % ANa-alg 15 25 38 65 84 B Na-alg 15 25 38 65 84 C HPMC 18 48 67 88 92

In vivo plasma profiles in humans, N=1 per composition

Dexamethasone suppression test, fasting state, otherwise as described inthe paragraph denoted “Method”.

The results show that the use of hydrocortisone acetate does not seem tobe suitable for an immediate release composition. This was furtherinvestigated in the following example.

Example 12 Non-Mucoadhesive Immediate Release Films

Two films were prepared essentially similar to Example 13—composition A.Film A contains 10 mg of hydrocortisone and film B contains 11.2 mg ofhydrocortisone acetate. The results from in vivo testing after buccaladministration are shown in FIGS. 4 and 5. The results show that even ifthe films are not bioadhesive, a fast onset of the absorption into thesystemic circulation after single dose administration of Film A isobtained. In contrast, the results obtained with the film containinghydrocortisone acetate indicate that this compound does not seem to besuitable when a fast onset of the absorption into the systemiccirculation of the glucocorticoid is required.

Example 13 Thin-Layer Films for Immediate Release

Batches of glucocorticoid films were prepared from the followingcompositions A and B:

Component % w/w Rapid-release composition A: PEG 400 2.0 Hydrocortisone3.0 Methocel E5 4.0 Xylitol 1.0 Water 90 Slower release composition B:PEG 400 1.3 Hydrocortisone 3.0 Methocel E5 5.7 Water 90

To distilled water (18 ml) in 50 ml round-bottomed glass flask providedwith a magnetic stirred was added Methocel E5. After the Methocel haddissolved completely PEG 400 was added under continued stirring,followed by xylitol (Composition A only) and hydrocortisone. Stirringwas continued for 4 h.

Into flat-bottomed PVC-blisters (Inpack AB, Lund, Sweden) 16 mm indiameter was pipetted (Finnpipette; automatic) 330 μl of solution A or Binto each blister trough. The solutions were allowed to dry at roomtemperature over night. The next day 10 films were removed for doseanalysis. Each film was dissolved in 100 ml of water/ethanol (95%) 9:1(w/w). The solutions were analysed by UV spectroscopy at 242 nm. Meancontents of 10.19 mg and 9.83 mg hydrocortisone per blister (SD 0.29 and0.14, respectively) were found for Compositions A and B, respectively.

The hydrocortisone compositions were tested in two human subjects afterlabial administration. The subjects had their endogenous glucocorticoidsecretion suppressed by synthetic glucocorticoids. The plasmaconcentration of cortisol was monitored during 360 min after the labialadministration, and the serum concentration time profiles from these twosubjects are shown in FIGS. 6 and 7.

It is clearly seen that the rate and extent of mucosal uptake ofhydrocortisone is high and the appearance of cortisol in serum is rapid,as the first measured plasma concentration was attained already at 10-15min.

These serum pharmacokinetic data illustrate that a formulation of theinvention for oral mucosa administration results in a high rate andextent of mucosal absorption of the active drug, even though a smallvolume of fluid is available for dissolution at the site ofadministration and absorption in this route drug delivery.

Example 14 Glucocorticoid Tablets for Immediate Release

Glucocorticoid tablets were manufactured by direct compression of thedry-mixed powderous components to the following composition C:

Component Per Batch Rapid-release composition C: PEG 6000 8.7 gHydrocortisone 2.5 g Xylitab 300 8.7 g Mg stearate 0.16 g 

Batch Size 100 Tablets

The powderous components were sieved (mesh size 0.7 mm) and dry-mixed byshaking by hand in a small tin can for five min. The homogeneity of themixture was analyzed by the same method as used for analysis of thetablets. Tabletting was carried out with a DIAF tabletting machine usinga flat circular punch 7 mm in diameter (with a dividing score). Thehydrocortisone dose in 10 tablets was assessed by the same method asused for the films. Mean contents of 9.53 mg hydrocortisone per tablet(SD 0.15) were found for composition C.

Tablet thickness (10 tablets): 1.72-1.76 mm (C);Friability (20 tablets): 0.6% (C);Tablet hardness (10 tablets): 23.7 N(C).

The compositions were tested after oral administration to two humansubjects (see FIG. 8).

The rate of absorption of the glucocorticoid into the systemiccirculation from the solid dosage forms of Example 14 was somewhatslower than that of compositions from Example 13, which means that it ispossible to adjust the absorption rate of hydrocortisone into thesystemic circulation by introducing changes in the composition andfunction of the labial pharmaceutical formulation.

Example 15 In Vitro Dissolution Profile

The in vitro dissolution profiles of hydrocortisone from drugformulations according to Example 20 and 21 were followed over time in astandardized controlled in vitro environment. A United StatesPharmacopoeia dissolution apparatus II (paddle) coupled to automaticsampling devices and software was used for acquiring release profiles ofthe drug formulations in a neutral pH environment. The dissolutionprofile was acquired at 37° C., 50 rpm of the paddles, in a total of 300ml of water. Sampling was performed at 0, 1, 3, 5, 7, 10 and 15 minutesfollowing the insertion of the pharmaceutical composition in the examplein the dissolution medium.

The dissolution profile from each formulation was monitored in twoexperiments up to 360 min after administration, and the correspondingdissolution time profiles are shown in FIGS. 9 and 10, respectively. Therelease rate is given as the percent of dose over time.

The release rate from the solid dosage forms of Example 21 was somewhatslower (FIG. 10). This means that it is possible to adjust the releaserate of hydrocortisone by introducing changes in the composition andfunction of the oronasopharyngeal pharmaceutical preparation.

1-89. (canceled)
 90. A pharmaceutical composition in solid or semi-solidform configured for systemic administration to a subject via thesubject's oral mucosa comprising one or more glucocorticoids forsubstantially immediate release and one or more pharmaceuticalacceptable excipients, wherein at least about 60% of the one or moreglucocorticoids are released from the composition with the first 10 minafter start of an in vitro dissolution test according to USP employingUSP Dissolution Apparatus No. 2 (paddle), 50 rpm and a suitabledissolution medium.
 91. A pharmaceutical composition according to claim90, wherein a glucocorticoid serum level of a subject of at least 20% ofC_(max) is reached within 20 min after administration of the compositionvia a mucosa of the subject.
 92. A pharmaceutical composition accordingto claim 90, wherein at least 40% of C_(max) is reached within 30 minafter administration of the composition via a mucosa of the subject. 93.A pharmaceutical composition according to claim 92, wherein at least 75%of C_(max) is reached within 45 min after administration of thecomposition via a mucosa of the subject.
 94. A pharmaceuticalcomposition according to claim 90, wherein T_(max) is reached within 60min after administration of the composition via a mucosa of the subject.95. A pharmaceutical composition according to according to claim 90,wherein one or more glucocorticoids are released from the compositionwithin the first 5 min of the dissolution test.
 96. A pharmaceuticalcomposition according to claim 90, wherein at least about 70% of the oneor more glucocorticoids are released from the composition within thefirst 15 min after start of the dissolution test.
 97. A pharmaceuticalcomposition according to claim 90, wherein at least about 80% of the oneor more glucocorticoids are released from the composition within thefirst 15 min after start of the dissolution test.
 98. A pharmaceuticalcomposition according to claim 97, wherein at least about 80% of the oneor more glucocorticoids are released from the composition within thefirst 10 min after start of the dissolution test.
 99. A pharmaceuticalcomposition according to claim 90, wherein at least about 90% of the oneor more glucocorticoids are released from the composition within thefirst 15 min after start of the dissolution test.
 100. A pharmaceuticalcomposition according to claim 90 designed for administration to theoral cavity.
 101. A pharmaceutical composition according to claim 90 inthe form of a solid dosage form.
 102. A pharmaceutical compositionaccording to claim 101, wherein the solid dosage form is selected fromthe group consisting of granules, beads, pellets and powders.
 103. Apharmaceutical composition according to claim 90 in unit dosage form.104. A pharmaceutical composition according to claim 103, wherein theunit dosage form is in the form of a tablet including a chewable tablet,a suckable tablet, an effervescent tablet, a sublingual tablet, a rapidburst tablet, an immediate release tablet, or a rapidly dissolvabletablet.
 105. A pharmaceutical composition according to claim 100 in theform of a spray, a wafer, a film, a gel, a hydrogel, a patch, a gingivalpatch, a bioadhesive patch, or a sachet.
 106. A pharmaceuticalcomposition according to claim 90, wherein the total amount of the oneor more glucocorticoids expressed as hydrocortisone is from about 1 toabout 200 mg.
 107. A pharmaceutical composition according to claim 106,wherein the total amount of the one or more glucocorticoids expressed ashydrocortisone is from about 1 to about 175 mg such as, e.g., from about1 to 150 mg, from about 1 to about 100 mg, from 1 to 75 mg, from about 1to about 70 mg, from about 1 to about 60 mg, from about 5 to about 50mg, from about 5 to about 40 mg or from about 10 to about 30 mg.
 108. Apharmaceutical composition according to claim 90, wherein the one ormore glucocorticoids is selected from the group consisting ofhydrocortisone, cortisone, prednisolone, prednisone, methylprednisone,triamcinolone, paramethasone, betamethasone, dexamethasone andfludrocortisone or mixtures thereof, including pharmaceuticallyacceptable esters, salts and complexes thereof.
 109. A pharmaceuticalcomposition according to claim 108, wherein the pharmaceuticallyacceptable salt is a phosphate, a succinate, a lysinate, an acetate, acypionate, a valerate, a hemisuccinate, a butyrate or a trometamolesalt.
 110. A pharmaceutical composition according to claim 108 in unitdosage form, wherein the one or more glucocorticoids are cortisone orhydrocortisone including pharmaceutically acceptable esters, salts andcomplexes thereof in an amount corresponding to from about 1-200.
 111. Apharmaceutical composition according to claim 108 in unit dosage form,wherein the one or more glucocorticoids are betamethasone includingpharmaceutically acceptable esters, salts and complexes thereof in anamount corresponding to from about 1 to about 20 mg.
 112. Apharmaceutical composition according to claim 108 in unit dosage form,wherein the one or more glucocorticoids are prednisolone includingpharmaceutically acceptable esters, salts and complexes thereof in anamount corresponding to from about 1 to about 10 mg.
 113. Apharmaceutical composition according to claim 108 in unit dosage form,wherein the one or more glucocorticoids are dexamethasone includingpharmaceutically acceptable esters, salts and complexes thereof in anamount corresponding to from about 0.1 to about 2 mg.
 114. Apharmaceutical composition according to claim 108 in unit dosage form,wherein the one or more glucocorticoids are fludrocortisone includingpharmaceutically acceptable esters, salts and complexes thereof in anamount corresponding to from about 0.05 to about 5 mg.
 115. Apharmaceutical composition according to claim 108 in unit dosage form,wherein the one or more glucocorticoids are prednisone includingpharmaceutically acceptable esters, salts and complexes thereof in anamount corresponding to from about 10 to about 50 mg.
 116. Apharmaceutical composition according to claim 108 in unit dosage form,wherein the one or more glucocorticoids are methylprednisolone includingpharmaceutically acceptable esters, salts and complexes thereof in anamount corresponding to from about 2 to about 20 mg.
 117. Apharmaceutical composition according to claim 90 in the form of a film,patch, wafer, gel, sachet, gingival patch, lozenge or the like.
 118. Apharmaceutical composition according to claim 117, wherein thecomposition comprises a pharmaceutically acceptable excipient selectedfrom the group consisting of an acrylic polymer including a derivativethereof, a cellulose derivative, modified starch, polyethylene oxide,chitosan, gelatin, sodium alginate, pectin, scleroglucan, xanthan gum,guar gum, or poly-co-(methyl vinyl ether-malefic anhydride), alone or incombinations thereof.
 119. A pharmaceutical composition according toclaim 118, wherein the cellulose derivative is selected from the groupconsisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, sodium carboxymethyl cellulose, methylcellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose,microcrystalline cellulose, modified cellulose gum, or crosscaramellose.120. A pharmaceutical composition according to claim 90 furthercomprising one or more bio/mucoadhesion promoting agents.
 121. Apharmaceutical composition according to claim 120, wherein the one ormore bio/mucoadhesion promoting agents are present in concentration offrom about 0.1 to about 25% w/w.
 122. A pharmaceutical compositionaccording to claim 120, wherein the one or more bio/mucoadhesionpromoting agents are a polymer including a synthetic polymer a naturalpolymer and a derivative thereof, and mixtures thereof.
 123. Apharmaceutical composition according to claim 122, wherein the polymeris selected from a carbomer, a polyethylene oxide, a polyco-(methylvinyl ether/maleic anhydride), and mixtures thereof.
 124. Apharmaceutical composition according to claim 122, wherein the polymeris a polysaccharide.
 125. A pharmaceutical composition according toclaim 124, wherein the polysaccharide is selected from the groupconsisting of gelatin, sodium alginate, pectin, scleroglucan, xanthangum, guar gum, microcrystalline cellulose, crosscaramellose,hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, ethyl hydroxyethyl cellulose,carboxymethyl cellulose, sodium carboxymethyl cellulose, moderatelycross-linked starch, and chitosan.
 126. A pharmaceutical compositionaccording to claim 90 further comprising a dissolution promoting agent.127. A pharmaceutical composition according to claim 126, wherein thedissolution promoting agent is present in a concentration of from about0.05 to about 5% w/w.
 128. A pharmaceutical composition according toclaim 126, wherein the dissolution promoting agent is selected from thegroup consisting of sodium lauryl sulphate, a polysorbate, a bile acid,a bile salt, a salt of cholic acid or cholanic acid, isopropylmyristate, methyl laurate, oleic acid, oleyl alcohol, glycerolmonoleate, glycerol dioleate, glycerol trioleate, glycerol monostearate,glycerol monolaurate, propylene glycol monolaurate, sodium dodecylsulfate, and a sorbitan ester.
 129. A pharmaceutical compositionaccording to claim 90, wherein the one or more glucocorticoids arepresent as microparticles or nanoparticles.
 130. A pharmaceuticalcomposition according to claim 129, wherein the mean particle size is 10um or less.
 131. A pharmaceutical composition according to claim 129,wherein the micro- or nanoparticles are encapsulated.
 132. Apharmaceutical composition according to claim 131, wherein the micro- ornanoparticles are encapsulated with a coating comprising a lechitin or alechitin based compound.
 133. A pharmaceutical composition according toclaim 90 further comprising a disintegrating agent.
 134. Apharmaceutical composition according to claim 133, wherein thedisintegrating agent is selected from the group consisting ofcross-linked polyvinylpyrrolidone, carboxymethyl starch, natural starch,microcrystalline cellulose, and cellulose gum.
 135. A pharmaceuticalcomposition according to claim 133, wherein the disintegrating agent ispresent in a concentration of from about 0.5 to about 10% w/w.
 136. Apharmaceutical composition according to claim 90 further comprising ataste-masking agent.
 137. A pharmaceutical composition according toclaim 136, wherein the taste-masking agent is selected from the groupconsisting of menthol, peppermint, vanillin, a terpene based compound,or an artificial sweetener.
 138. A pharmaceutical composition accordingto claim 90, wherein the one or more glucocorticoids are taste masked byincorporation into an inclusion complex by means of alpha-, beta-, orgamma-cyclodextrins, preferably by beta-cyclodextrins.
 139. Apharmaceutical composition according to claim 90 for buccaladministration.
 140. A pharmaceutical composition according to claim 139in the form of a gel, a gum, a wafer, a thin-layer film, a patch, agingival patch, a tablet, a sachet, a lozenge, a fast-dissolving tablet,a cream or an ointment.
 141. A kit for treating a subject suffering froma disorder requiring acute glucocorticoid therapy comprising one or morecontainers for housing a pharmaceutical composition according to claim90, and instructions for use thereof.
 142. A kit according to claim 141,wherein the one or more containers are in the form of blisters orblister packs.
 143. A method for treating a subject suffering from adisorder requiring acute glucocorticoid therapy, the method comprising:administering via the mucosa of the oral cavity of the subject aneffective amount of a pharmaceutical composition as recited in claim 90to obtain a fast rise in the glucocorticoid serum level to at least 20%of C_(max) within 20 min after administration.
 144. A method accordingto claim 143, wherein at least 40% of C_(max) is reached within 30 minafter administration.
 145. A method according to claim 143, wherein atleast 75% of C_(max) is reached within 45 min after administration. 146.A method according to claim 143, wherein T_(max) is reached within 60min after administration of the composition via a mucosa of the subject.147. A method according to claim 143, wherein the disorder requiringacute glucocorticoid therapy is an acute adrenal crisis.
 148. A methodaccording to claim 147, wherein the acute adrenal crisis relates to aprimary, secondary, or tertiary adrenal insufficiency, an anaphylacticreaction, an Addison crisis, a status asthmaticus, a blood transfusionreaction, ab rain edema, a severe allergic reaction, acute asthma, acuteanaphylaxia, septic shock, acute bacterial meningitis, acute RSV(respiratory syncytial virus) infection with bronchiolitis in children,acute croup-children, mononucleosis with complications (airwayobstruction, thrombocytopenia or haemolytical anemia), ortonsillitis/peritonsillitis in children with airway obstruction.
 149. Amethod according to claim 143, wherein the disorder requiring acuteglucocorticoid therapy relates to an inflammatory disorder, anautoimmune disorder, or a medical disorder in which a glucocorticoidforms a part of the first line emergency medial treatment or intenseshort-time medical treatment.
 150. A method according to claim 143,wherein the effective amount of the one or more glucocorticoidsexpressed as hydrocortisone is from about 1 to about 200 mg.
 151. Amethod according to claim 150, wherein the effective amount of the oneor more glucocorticoids expressed as hydrocortisone is from about 1 toabout 175 mg such as, e.g., from about 1 to about 150 mg, from about 1to about 125 mg, from about 1 to about 100 mg, from about 1 to about 75mg, from about 1 to about 70 mg, from about 1 to about 60 mg, from about5 to about 50 mg, from about 5 to about 40 mg or from about 10 to about30 mg.
 152. A method according to claim 143, wherein the one or moreglucocorticoids is selected from the group consisting of hydrocortisone,cortisone, prednisolone, prednisone, methylprednisone, triamcinolone,paramethasone, betamethasone, dexamethasone and fludrocortisone ormixtures thereof, including pharmaceutically acceptable esters, saltsand complexes thereof.
 153. A method according to claim 153, wherein thepharmaceutically acceptable salt is a phosphate, a succinate, alysinate, an acetate, a cypionate, a valerate, a hemisuccinate, abutyrate or a trometamole salt.
 154. A method according to claim 143,wherein the effective amount of the one or more glucocorticoid iscontained in a pharmaceutical composition suitable for administration bythe subject itself or by non-medically trained persons.
 155. A methodaccording to claim 154, wherein the composition is in a form that can beadministered to the subject even if he is unconscious.
 156. A methodaccording to claim 154, wherein the composition is in a form that can beadministered to the subject and have effect even if he is unable toswallow the composition.
 157. A method according to claim 143, whereinthe one or more glucocorticoids are cortisone or hydrocortisoneincluding pharmaceutically acceptable esters, salts and complexesthereof and wherein the effective amount is in a range of from about 1to about 100 mg.
 158. A method according to claim 143, wherein the oneor more glucocorticoids are betamethasone including pharmaceuticallyacceptable esters, salts and complexes thereof and wherein the effectiveamount is in a range of from about 1 to about 20 mg.
 159. A methodaccording to claim 143, wherein the one or more glucocorticoids areprednisolone including pharmaceutically acceptable esters, salts andcomplexes and wherein the effective amount is in a range of from about 1to about 10 mg.
 160. A method according to claim 143, wherein the one ormore glucocorticoids are dexamethasone including pharmaceuticallyacceptable esters, salts and complexes and wherein the effective amountis in a range of from about 0.1 to about 2 mg.
 161. A method accordingto claim 143, wherein the one or more glucocorticoids arefludrocortisone including pharmaceutically acceptable esters, salts andcomplexes and wherein the effective amount is in a range of from about0.05 to about 5 mg.
 162. A method according to claim 143, wherein theone or more glucocorticoids are prednisone including pharmaceuticallyacceptable esters, salts and complexes and wherein the effective amountis in a range of from about 10 to about 50 mg.
 163. A method accordingto claim 143, wherein the one or more glucocorticoids aremethylprednisolone including pharmaceutically acceptable esters, saltsand complexes and wherein the effective amount is in a range of fromabout 2 to about 20 mg.
 164. Use of a pharmaceutical composition asdefined in claim 90 for the preparation of a medicament for thetreatment of a disorder requiring acute glucocorticoid therapy byproviding a fast rise in the glucocorticoid serum level to at least 20%of C_(max) within 20 min after administration via the mucosa of the oralcavity.
 165. Use according to claim 164, wherein at least 40% of C_(max)is reached within 45 min after administration.
 166. Use according toclaim 164, wherein at least 75% of C_(max) is reached within 45 minafter administration.
 167. Use according to claim 164, wherein T_(max)is reached within 60 min after administration of the composition via amucosa of the subject.
 168. Use according to claim 164, wherein thepharmaceutical composition is suitable for administration by the subjectitself or by non-medically trained person.
 169. Use according to claim164, wherein the pharmaceutical composition is in a form that can beadministered to the subject even if he is unconscious.
 170. Useaccording to claim 168, wherein the pharmaceutical composition is in aform that can be administered to the subject and have effect even if heis unable to swallow the composition.